Diagnostic imaging radiopharmaceuticals based on the radioisotope technetium-99m (99mTc) are known for a variety of clinical diagnoses, including functional studies (eg. renal), and perfusion (especially heart and brain). The radioisotope 99mTc has a half-life of 6 hours, hence such 99mTc radiopharmaceuticals are usually prepared from so-called “kits”.
These kits for the preparation of 99mTc radiopharmaceuticals permit the user to maintain stocks of non-radioactive kits, which are designed to be reconstituted with 99mTc-pertechnetate (TcO4) from a supply of 99mTc. A sterile solution of 99mTc-pertechnetate in isotonic saline is obtained by elution of a technetium generator with sterile saline as is known in the art.
Kits for the preparation of 99mTc radiopharmaceuticals typically contain:                (i) a ligand which forms a metal complex with 99mTc,        (ii) a biocompatible reducing agent capable of reducing pertechnetate, ie. Tc(VII) to the lower oxidation state of the desired 99mTc metal complex product.        
The biocompatible reducing agent for the 99mTc pertechnetate is typically stannous ion, ie. Sn(II). The kit may contain additional excipients, such as weak chelating agents (such as gluconate, glucoheptonate, tartrate or EDTA), stabilisers, pH-adjusting agents, buffers, solubilisers or bulking agents (such as mannitol, inositol or sodium chloride), to facilitate handling and lyophilisation of the kit components. To facilitate storage and distribution, the non-radioactive kits are usually supplied freeze-dried in a sterile vial with closure. The lyophilised formulation also permits facile reconstitution by the end users with sterile pertechnetate in saline, to give the desired sterile, injectable 99mTc radiopharmaceutical for human use. The shelf life of the non-radioactive technetium kit may be several months.
Radiopharmaceutical compositions may suffer from radiolysis, particularly of the solvent (typically water), with consequent generation of highly reactive free radicals, which may degrade one or more components of the composition. It is known to employ radioprotectants or free radical scavengers to help suppress such degradation. Typically, free radical scavengers are taken from known classes of antioxidant compounds. Ascorbic acid and ascorbates are disclosed to function as stabilisers for stannous-containing non-radioactive kits for the preparation of 99mTc radiopharmaceuticals in U.S. Pat. No. 4,364,920, and have subsequently been widely used in 99mTc radiopharmaceutical preparations. Gentisic acid stabilisers for 99mTc radiopharmaceuticals are disclosed in U.S. Pat. No. 4,233,284. Para-aminobenzoic acid (PABA) and related stabilisers for 99mTc radiopharmaceutical preparations are disclosed in U.S. Pat. No. 4,451,451.
U.S. Pat. No. 3,939,258 (1976) teaches that the antimicrobial preservatives methylparaben and propylparaben can be added to radiopharmaceutical preparations containing the radioisotope 113In. The preparations do not contain a radioprotectant.
The commercial non-radioactive kit CHOLETEC™ for the preparation of a 99mTc radiopharmaceutical, contains mebrofenin (4.5 mg), methylparaben (4.5 mg), propylparaben (0.5 mg) and stannous fluoride (0.73 mg) in the formulation. The kit formulation does not contain a radioprotectant. The pack leaflet also includes the statement that “If sodium pertechnetate Tc-99m injection must be diluted for use with Choletec, only Sodium Chloride Injection USP without preservatives should be used.” Mebrofenin is a complexing agent for 99mTc, which is a substituted iminodiacetic acid (IDA).
The parabens are a known series of antimicrobial preservatives:
                R═Me Methylparaben                    Et Ethylparaben            n-Pr Propylparaben            n-Bu Butylparaben                        
U.S. Pat. No. 5,093,105 relates to the use of benzalkonium chloride or benzethonium chloride as radiopharmaceutical antimicrobial preservatives, which are claimed to be compatible with radioprotectants. Other antimicrobial preservatives are described in U.S. Pat. No. 5,093,105 as being incompatible with radioprotectants. Benzethonium chloride is, however, classed as a weak carcinogen and benzalkonium chloride is generally regarded as a toxic substance when administered orally.
Hensel et al. [J Pharm Sci 1995; 84(1):115–118] disclose that the degradation of paraben preservatives in the presence of macromolecules such as polysaccharides, and specifically via transesterification with alcohols, was a known problem. They reported that transesterification of parabens also occurs in the presence of polyols, such as xylitol, glycerol and sorbitol, but did not observe transesterification with aldoses such as ribose or xylose.
Certain radiopharmaceutical agents are particularly useful to be available in an acute situation, eg. an intensive care or emergency room (ER) setting. There is a need for some patient diagnoses to be made at any time of day or night, with ready availability of the radiopharmaceutical for the diagnostic scan, at times when conventional supply of radiopharmaceutical from a radiopharmacy may simply not be an option. For such purposes in particular, there is therefore a need for radiopharmaceuticals which can be prepared by a skilled radiopharmacist, but have a post-reconstitution shelf life of more than 12 hours, eg. up to 36 hours.